NO873626L - PROCEDURE FOR PREPARING PHARMACEUTICAL PHARMACEUTICAL PREPARATIONS OF PHENYLKINOLINE CARBOXYL ACIDS. - Google Patents

Description

The invention relates to the production of freeze-dried pharmaceutical preparations and stable aqueous injectable preparations which can be reconditioned from these. More specifically, the invention relates to the production of such preparations where bile acid salts are used in the stabilization system for phenylquinoline carboxylic acids with antitumor activity.

Phenylquinoline carboxylic acids are described as antitumor agents in US patent application no. 727 808. These agents are also described in EP patent application no. 133 244. However, to avoid contamination or the risk of spillage or aerosol inhalation during ampoule opening, a freeze-dried powder is preferred dosage form for these agents.

In order to produce a freeze-dried product, it is necessary to make a medicinal solution that can be filtered, filled in suitable containers and lyophilized so that a perfectly shaped piece is formed. After being reconditioned, the drug solution should also be free of particles and ready for intravenous administration.

The phenylquinoline carboxylic acids are insoluble in water when they are in acid form. The solutions prepared with the salts of the acids are unstable and tend to form precipitates after a short time. Precipitation occurs even at a concentration as low as 100 ug/ml, while a solution of up to 125 mg/ml is needed for product manufacture. It is obvious that solubilizing agents are needed which can increase the solubility of these phenylquinoline carboxylic acids.

Solubilization techniques are known in the art, but such techniques depend on the drugs being formulated.

For example, the use of a cosolvent or a complexing agent to increase drug solubility was found useful in some pharmaceutical applications. Such examples can be found in "Techniques of Solubilization of Drugs", edited by S. H. Yalkowsky, Chapter 3, page 91. However, these techniques are not practical for the preparation of freeze-dried preparations that are reconditioned into intravenous products. Co-solvents such as ethyl alcohol, benzyl alcohol and propylene glycol can, for example, solubilize a drug to a desired concentration, but due to the liquid form of these co-solvents, the preparation of freeze-dried powders with these co-solvents is difficult. Attempts to use a complexing agent, such as niacinamide, up to a physiologically acceptable concentration with phenylquinoline carboxylic acids do not act to prevent the acids from precipitating.

Another method that has been used to improve the solution stability of certain drugs is to use micelle solubilization techniques with suitable solubilizers. However, identifying a suitable solubilizer is a challenging task in the manufacture of parenteral preparations, as micelles from each solubilizer behave differently. For example, the micelles formed from some commonly used solubilizing agents, such as Tween<®>20, Tween<®>80, Emulphor<®>719P and Pluronic<®>F-68, do not have sufficient solubilizing capacity to prevent the phenylquinoline carboxylic acids from is precipitated. Moreover, incorporation of these solubilizing agents into the parenteral formulation may either result in a change in drug activity due to the incorporation of the drug into the hydrophobic micelle core, or cause toxicity to

increase due to the surface activity of these solubilizing agents.

US Patent No. 4,478,829 describes the use of bile acid salts as surfactants in the same category as the surfactants "polysorbates", Triton<®>X100

and Pluronic<®>F-68, in the preparation of lyophilized fibronectin which is easily reconditioned with sterile water. Likewise, the bile acid salt sodium deoxycholate is described in EP patent application no. 141922-A1 in combination with freeze-drying to reduce turbidity in reconditioned clinical control sera.

US Patent No. 4,036,954 describes the use of

a salt of deoxycholic acid as an additive in the lyophilization of a compound belonging to the prostaglandin E group.

It is known that the freeze-drying technique can be used for

to convert a medicinal preparation from an aqueous mixture into a solid form. It is surprising to find that according to the present invention the phenylquinoline carboxylic acid compounds with antitumor activity can be successfully formulated into stable aqueous injectables.

only preparations by using a specially selected type of soluble lubricant together with the freeze-drying technique.

According to the present invention, a method is provided for the production of a pharmaceutical preparation in powder form which is suitable for reconditioning into a parenteral solution consisting essentially of a freeze-dried mixture of (a) a salt of a drug which in free acid form has a water- solubility in the ug/ml range at room temperature, and (b) a stabilization system consisting essentially of (1) a bile acid salt and (2) a pharmaceutically acceptable base or buffer which will provide a pH in the range of 8.5 - 11 after water -reconditioning, as the weight ratio between (a) and (b)(1) is at least 1:0.1.

A method for the production of a stable injectable pharmaceutical preparation is also provided which comprises an aqueous solution of a part by weight of a salt of a drug which in free acid form has a water solubility in the ug/ml range at room temperature, at least 0.1 part by weight of a bile acid salt per drug part, and sufficient pharmaceutically acceptable base or buffer to give a pH in the range of 8.5 - 11.

In connection with the present invention, it has been discovered that bile acid salts, which are major breakdown products of cholesterol in humans, are useful solubilizing agents to prevent salts of phenylquinoline carboxylic acids from precipitating during the preparation of a large batch of a solution and after reconditioning from the freeze-dried form. . Drug solutions prepared with these solubilizing agents are stable and can be easily freeze-dried so that perfectly shaped pieces are formed without any change in strength. After being reconstituted with water for injection, the solution remained clear and suitable for intravenous administration. Further investigations also indicated that there is little change in drug activity and toxicity when the drug and the solubilizing agents for the bile acid salt were dissolved together in the solution.

The freeze-dried preparation in powder form described here essentially consists of an active anti-tumor ingredient, a salt of a phenylquinoline carboxylic acid, preferably the sodium salt of 6-fluoro-2-(2'-fluoro-1'-biphenyl- 4-yl)-3-methyl-4-quinolinecarboxylic acid or 2-(1,1<1->biphenyl-4-yl)-5-chloro-3-methyl-4-quinolinecarboxylic acid, and a stabilization system. The stabilization system essentially consists of a dissolving agent for bile acid salt and a pharmaceutically acceptable buffer or base which will regulate the pH to 8.5 - 11 in water solution.

Although any salt of the phenylquinoline carboxylic acids disclosed in EP Patent Application No. 133,244

can be used, the preferred acid salts are those described above.

The bile acid salts that can be used in the stabilization system are preferably sodium cholate or sodium deoxycholate. Other alkali metal salts (lithium, potassium) or organic salts can also be used. Salts of other bile acids can also be used. These include dehydrocholic acid, lithocholic acid, hydrodeoxycholic acid, chenodeoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycocholic acid and taurocholic acid.

Any pharmaceutically acceptable base or buffer can be used in the compositions, provided they provide an initial pH in water or a pH after water reconditioning in the range of 8.5 - 11, preferably pH of about 9. Useful buffers and bases include sodium glutamate, sodium phosphate, glycine, sodium hydroxide, triethanolamine and sodium carbonate. Preferred substances are glycine or sodium hydroxide. Glycine is particularly preferred.

The amount of substances in the preparations depends on the medicine, e.g. the salt of a phenylquinolinecarboxylic acid. For every 1 part by weight of the medicine, approx. 0.1 part by weight of bile acid salt. Generally, the preferred weight ratio of drug to bile acid salt is in the range of 1:0.1 to 1:0.8.

The invention is further illustrated by means of

the following examples.

Example 1

Freeze-dried preparation containing the sodium salt of 6-fluoro-2-(2'-fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid Each 10 ml ampoule contained 100 mg of the title compound, 40 mg of sodium cholate and 40 mg glycine.

For the manufacture of 250 ampoules:

25 g of the title compound was suspended in a solution of 10 g of sodium cholate and 10 g of glycine in 950 ml of water for injection. The pH of the resulting suspension was adjusted to 9.0-9.5 with 1 N NaOH and the mixture was stirred until clear. The solution was then adjusted to 1000 ml by adding water for injection with stirring and then filtering through a 0.22 µm filter. Each 10 ml vial was aseptically filled with 4 ml of the filtered solution.

The ampoules were placed in a lyophilizer and frozen to -40 to -45°C within 2 hours. The condenser was switched on and the temperature reached -60° C. The ampoules were then evacuated to 50 - 100 milliTorr at 20° C for 24 hours.

Finally, the ampoules were dried at 45°C for a further 2 hours, yielding a perfectly shaped white piece which was reconstituted with 4 ml of water for injection into a stable solution for intravenous use.

The 24 hour stability data for the reconstituted solution of the title compound is shown in Table I.

Drug concentrations were determined using high-pressure liquid chromatography (HPLC). The average values are based on four separate aliquots taken from a composite sample.

Example 2

Freeze-dried preparation containing the sodium salt of 2-(1,1'-biphenyl-4-yl)-5-chloro-3-methyl-4-quinolinecarboxylic acid

Each 10 ml vial contained 100 ml of the title compound, 50 mg sodium deoxycholate and 50 mg glycine.

This preparation was prepared in a similar manner to that described in example 1. A powder with similar properties was obtained.

Example 3

Freeze-dried preparation containing the sodium salt of 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid

Each 10 ml vial contained 100 mg of the title compound, 80 mg of sodium cholate and sufficient sodium hydroxide to obtain a pH of 9.0.

This preparation was prepared in a manner similar to that described in example 1. A powder with similar properties was obtained.

Example 4

Freeze-dried preparation containing the sodium salt of 6-fluoro-2-(2'-fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid

Each 20 ml ampoule contained 500 mg of the title compound, 80 mg of sodium cholate and 80 mg of glycine.

For the manufacture of 250 ampoules:

125 g of the title compound was slurried in a solution of 20 g of sodium cholate and 20 g of glycine in 1195 ml of water for injection. The pH of the resulting suspension was adjusted to 9.0-9.5 with 1 N NaOH and the mixture was stirred until clear. The solution was then adjusted to 2000 ml by adding water for injection with stirring and then filtering through a 0.22 µm filter. Each 20 ml vial was aseptically filled with 8 ml of the filtered solution.

The ampoules were placed in a lyophilizer and frozen to -40 to -45°C within 6 hours. The condenser was switched on and the temperature now reached -60° C. The ampoules were then evacuated to 50 - 100 milliTorr at 20° C within 24 hours. Finally, the ampoules were dried at 45° C for a further 4 hours, whereby a perfectly shaped white piece was obtained which was reconditioned with 8 ml of water for injection to a stable solution for intravenous use.

Example 5

Stability studies on freeze-dried sodium salt of 6-fluoro-2-(2'-fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid

The title compound was formulated as described in Example 1. The freeze-dried powder was sealed in 10 ml ampoules and stored under different conditions for stability observation. As shown in Table II, the formulated samples are chemically stable. However, upon visual inspection, a light brown color developed after exposure to bright light.

Example 6

In vivo antitumor activity of the sodium salt preparation of 6-fluoro-2-(2'-fluoro-1,1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid

1 ml of a solution containing 25 mg of the title compound, 10 mg of sodium cholate and 10 mg of glycine was prepared with the same composition as in the reconstituted solution described in Example 1. Then 4 ml of distilled water was added to make 50 mg/kg resolution. Two-fold serial dilutions were made in distilled water from the 50 mg/kg solution for the remaining three concentrations. An unformulated control solution was prepared by dissolving the title compound in distilled water and was used while ready.

The antitumor activity of the formulated and non-formulated material against L1210 leukemia in mice is shown in Table III. The test was carried out in the following way. On day 0, CDF1 mice were injected with 1 x 10 5 L1210 murine leukemia cells intraperitoneally. On day 1, formulated and unformulated title compound were injected intraperitoneally and injections continued once daily through day 9. Mice were observed until they died.

These experimental results show that sodium cholate and glycine have no effect on the antitumor activity of the title compound.

Example 7

Safety comparison of formulated sodium salt of 6-fluoro-2-(2'-fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid in distilled water and in 1% sodium cholate/ 1% glycine

A comparison experiment was carried out on the title compound to assess possible mortality differences between the preparations described here and preparations prepared by dissolving in water. The title compound was formulated into a freeze-dried preparation as in Example 1 and reconditioned with water before injection. The two solutions of the title compound were administered parenterally to female BgC-jF-^ mice weighing between 17 and 22 g, at single doses of 0, 120, 144, 173 and 200 mg/kg. After administration of the compound, mortality was assessed twice daily for 14 days.

LDr .. values, their corresponding 95% confidence inter-b U

dykes and the slope of the response curves were as follows:

In addition, ten female BgC-jF^ mice were given a single dose of the 1% sodium cholate/glycine (pH = 9.0) vehicle intravenously at 10 ml/kg. No mortality was observed as a result of this vehicle control administration.

Claims (12)

1. Process for the production of a pharmaceutical preparation in powder form which is suitable for reconditioning into a parenteral solution, characterized in that a freeze-dried mixture is produced of (a) a salt of a drug which in free acid form has a water solubility in the ug/ml range at room temperature, and (b) a stabilization system which essentially consists of (1) a bile acid salt and (2) a pharmaceutically acceptable base or buffer which will give a pH in the range of 8.5 - 11 after reconditioning with water, the weight ratio between (a) and (b) (1) being at least 1:0.1. 2. Method according to claim 1, characterized in that the weight ratio between (a) and (b)(1) is in the range 1:0.1 - 1:0.8. 3. Method according to claim 2, characterized in that the bile acid salt (b)(1) is a salt of cholic acid or deoxycholic acid. 4. Method according to claim 3, characterized in that the base or buffer (b)(2) is glycine or sodium hydroxide in sufficient quantity to give a pH of approx. 9 after reconditioning with water. 5. Method according to claim 4, characterized in that the drug is a sodium or potassium salt of a phenylquinoline carboxylic acid. 6. Process according to claim 5, characterized in that the phenylquinolinecarboxylic acid salt is the sodium salt of 6-fluoro-2-(2 <1-> fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid or 2- (1,1'-biphenyl-4-yl)-5-chloro-3-methyl-4-quinolinecarboxylic acid. 7. Method for the production of a pharmaceutical preparation in powder form which is suitable for reconditioning into a parenteral solution, characterized in that a freeze-dried mixture is prepared of (a) 1 part by weight of the sodium salt of 6-fluoro-2-(2 <1-> fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid and (b) a stabilization system consisting essentially of (1) 0.1 - 0.8 parts by weight sodium cholate and (2) a sufficient amount of glycine to provide a pH of about 9 after reconditioning with water. 8. Process for the production of a stable, injectable pharmaceutical preparation, characterized in that a preparation is produced which comprises: a water solution of 1 part salt of a drug which in free acid form has a water solubility in the pg/ml range at room temperature, at least 0.1 part by weight of a bile acid salt per drug part, and a sufficient amount of pharmaceutically acceptable base or buffer to give a pH in the range of 8.5 - 11. 9. Method according to claim 8, characterized in that the bile acid salt is sodium cholate or sodium deoxycholate at a weight concentration in the range 0.1 - 0.8 parts per drug part. 10. Method according to claim 9, characterized in that the base or buffer is glycine or sodium hydroxide in sufficient quantity to give a pH of approx. 9. 11. Method according to claim 10, characterized in that the drug is a sodium or potassium salt of a phenylquinoline carboxylic acid. 12. Method according to claim 11, characterized in that the phenylquinolinecarboxylic acid salt is the sodium salt of 6-fluoro-2-(2'-fluoro-1'-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid or 2-(1 ,1'-biphenyl-4-yl)-5-chloro-3-methyl-4-quinolinecarboxylic acid.